2-hydroxymethylene-17alpha-ethinyl-17beta-hydroxy-19-nor-4-androsten-3-one



United States Patent This invention relates to compounds of thenorandrostan-e series. More particularly, it relates toZ-hydroxymethylene 17a ethinyl 17B hydroxy 19 nor 4- androsten-3one ofthe formula ogen HOCH:

and to methods for its production.

In accordance with the invention 2-hydroxymethylene-17a-ethinyl-17fi-hydroxy-19-nor-4-androsten-3-one can be produced byreacting 17a-ethinyl-17fi-hydroxy19-nor-4- androsten-3-one with a loweralkyl formate in the presence of an alkali metal base, followed byacidifying the reaction product. The alkali metal base can be the metalitself or a basic derivative of the metal, such as the hydride, amide oralkoxide. Sodium hydride is the preferred agent. The reaction can becarried out with a lower alkyl formate such as ethyl formate, bystirring the reagents in an unreactive solvent such as tetrahydrofuran,diethyl ether, dipropyl ether, benzene, or mixtures thereof. Thereaction proceeds readily at room temperature and is substantiallycomplete within a period of from 24 to 48 hours. The reaction can alsobe carried out at other temperatures between 0 and 100 C., or theboiling point of the selected solvent, by varying the reaction time. Thereagents can be used in equimolar quantities, although it is preferableto use an excess of sodium hydride and the alkyl formate in order toobtain the best conversion of the steroidal starting material. Thereaction mixture contains the product in the form of an alkali metalsalt, and the 2-hydroxymethylene-17a-ethinyl-17f3-hydroxy-19-nor-4-androsten-3-one is obtained by acidification,preferably after dilution of the mixture with water and removal of theorganic solvent.

The product of this invention has useful pharmacological properties. Ithas hypocholesteremic activity and 3,256,302 Patented June 14, 1966 uponoral or parenteral administration produces a marked fall in the level ofblood cholesterol with relative freedom from side effects, such asestrogenic activity, which limit the usefulness of otherhypocholesteremic agents.

The invention is illustrated but not limited by the following example:

Example A solution of 5 g. of 17a-ethinyl-17fl-hydroxy-19-nor-4-androsten-3-one in ml. of dry tetrahydrofuran is treated with 2.9 g.of sodium hydride (5.8 g. of a 50% dispersion of'sodium hydride inmineral oil) and 5.5 g. of ethyl formate, and the mixture is stirred for24 hours, preferably in a nitrogen atmosphere. An additional 4.6 g. ofethyl formate is added and the stirring continued for 24 more hours. Themixture is treated dropwise with 100 ml. of water and thetetrahydrofuran removed by distillation under reduced pressure. Theremaining mixture is stirred with 1 liter of water and the insolublematerial removed by filtration. The filtrate, which contains the desiredproduct in the form of the sodium salt, is cooled and acidified withdilute hydrochloric acid to precipitateZ-hydroxymethylene-17a-ethinyl-17,8-hydroxy- 19-nor-4-androsten-3-one; ayellow-orange solid, M.P. about C. with prior softeningafter'crystallization from ether.

Alternatively, the product can also be obtained in the following manner.The dark yellow sodium salt formed in the reaction is filtered from thetetrahydrofuran and dried. The sodium salt is then dissolved in Waterand the solution filtered and acidified with dilute hydrochloric acid toprecipitate Z-hydroxymethylene-17a-ethinyl-17,8-hydroxy-l9-nor-4-androsten-3-one.

I claim:

2 hydroxymethylene 17a ethinyl 17B hydroxy- 19-nor-4-androsteu-3-one.

References Cited by the Examiner UNITED STATES PATENTS 2,908,69310/1959' Ringold et a1. 260397.4 3,118,915 1/1964 Ringold et a1 260397.43,135,743 6/1964 Clinton et a1. 260-23955 OTHER REFERENCES Fieser etal.: Steroids, p. 592 (1959), Reinhold Pub. Co., New York.

LEWIS GOTTS, Primary Examiner. LESLIE H. GASTON, Examiner.

G. E. LANDE, HENRY A. FRENCH,

Assistant Examiners.

